Discussion
We present a case of refractory KMT2A -r infantile leukemia that underwent multiple lineage switches during therapy, both with and without immunotherapeutic pressure. The underlying mechanism by whichKMT2A -r leukemia can lineage switch is not fully understood. Recent single cell sequencing studies suggest that some patients withKMT2A -r B-ALL harbor subpopulations of blasts that contain myeloid transcriptional profiles, which can become the dominant clone under the selective pressure of therapy.2,3 It is also described that in mixed phenotype acute leukemia, even distinct phenotypic populations, retain multilineage potential, rather than simple outgrowth of a minor clone.14 The frequently shifting leukemia immunophenotype presented a challenge for measuring MRD using flow-cytometry based methods. In this case, identifying and sequencing the clonal Ig rearrangements allowed for disease detection throughout therapy despite lineage switching. However, rearrangements ofKMT2A often occur prior to VDJ recombination and result in oligoclonal IG/TCR rearrangements15, which limits the broader utility of this approach for tracking MRD in KMT2A -r B-ALL. Alternatively, quantitative PCR based approaches for tracking the underlying KMT2A rearrangements have been suggested.16
KMT2A rearrangements confer poor prognosis in B-ALL17 and, when combined with detectable disease after consolidation, portend high risk of relapse.16Recent genomic analysis suggests that the immature differentiation state of KMT2A-r blasts may partially explain this poor therapeutic response through resistance to steroids.3 Our patient did not achieve remission at any point during initial therapy with standard cytotoxic agents, nor did she achieve meaningful benefit from the addition of the BCL-2 inhibitor venetoclax.
Given the lineage infidelity of her disease, she was treated with combinations of agents to target both the myeloid and lymphoid compartments. Initially, she received therapy containing blinatumomab (bispecific CD19/CD3 monoclonal antibody) and gemtuzumab (anti-CD33 monoclonal antibody conjugated to calicheamicin), which has demonstrated activity in cases of mixed phenotype acute leukemia.13,18 She did not achieve a clinically meaningful benefit from this combination, despite her blasts expressing both CD19 and CD33. However, the dominant blasts emerging from this therapy lost expression of the CD19 antigen in response to the blinatumomab and her disease did not regain expression of CD19 throughout the rest of her therapy.
The results of Interfant-06 determined that children with high end of induction MRD benefit from an intensive myeloid-directed chemotherapy backbone.19 These results, in combination with our experiences of frequent lineage switching in this patient, led us to treat her with a novel combination of liposomal daunorubicin + cytarabine (CPX-351) in combination with inotuzumab (anti-CD22 monoclonal antibody conjugated to calicheamicin). This was the only therapy she received that achieved remission, albeit with low level molecular evidence of disease still present.
The growing list of immunotherapeutic approaches provides opportunities to explore different combinations to improve disease control in infants with KMT2A -r B-ALL, potentially with improved safety profile in this patient group, who have inherently higher risk of treatment related toxicity. Along these lines, the addition of blinatumomab to the backbone of interfant-06 therapy showed improved survival in a recently published trial of KMT2A-r infantile leukemia20. The rise of single-cell genomic analysis may eventually lead to better prediction tools to help select which patients with KMT2A-r leukemia would respond to a lymphoid, myeloid, or combinatorial directed therapy.
This case highlights the challenges in treating KMT2A -r infantile B-ALL. The infidelity of KMT2A-r leukemias to either myeloid or lymphoid lineages presents unique challenges with respect to monitoring disease response by flow-based analysis. The inherent treatment resistance and poor prognosis emphasize the need to study novel combinatorial therapeutic strategies.